Chattanooga, Tennessee, about 120 miles (190 km) from both Huntsville and Knoxville, in opposite directions, is nicknamed "The Scenic City" for its beautiful views of the Tennessee Valley from atop the many mountaintops that surround the city. Chattanooga and its suburbs form the second most populous metropolitan area in the valley. The Battle of Chattanooga was fought on nearby Lookout Mountain. Chattanooga is also well known for the Chattanooga Choo-Choo, its transformation from a declining early industrial city to a thriving modern city, the famous Delta Queen, and the first publicly available one gigabit per second Internet access from a municipally-owned utilities company, i.e. the Electric Power Board (EPB), in the United States.

Decatur, Alabama, known as "The River City", dominated the economic landscape of north Alabama until the late 1950s, when the space race catapulted its neighbor Huntsville into that position. For most of the 20th century up to that point, Decatur held the top position in terms of economic impact and population. Its mixture of river transport and rail access has made it a busy hub of business, commerce, and manufacturing (chemicals and textiles especially) flowing down the river on the barges and boats of numerous companies and docking at the Port of Decatur. Decatur also claims the nickname "The Heart of the Valley" because of its location near the exact center of the length of the Tennessee River. Also because most north/south shipping traffic is funneled through the town utilizing three river crossings that are main routes for rail and road traffic between Birmingham and Nashville. The city is also an important river port that uses intermodal facilities to switch shipping methods between trains, trucks, and barges.

Guntersville, Alabama, is a major city of northeast Alabama and has a major lake and river port, Lake Guntersville and the Port of Guntersville, respectively. The city is famous for being the place where Ricky Nelson played his last concert before dying in a plane crash on New Year's Eve 1986 (December 31, 1985).

Muscle Shoals, Alabama, considered part of the Shoals along with Florence, Sheffield, and Tuscumbia, is a major city of northwest Alabama, along U.S. Route 72 and Alabama 157. The city is located immediately across the Tennessee River from Florence. (The river divides Colbert County from Lauderdale County.) Muscle Shoals is famous for its 1960s Muscle Shoals Sound, produced at such studios as FAME Studios and Muscle Shoals Sound Studio, where many famous musicians and bands, such as Aretha Franklin, Bob Dylan, and The Rolling Stones, also have recorded and produced numerous songs. Tuscumbia is the birthplace of Helen Keller. The original Congressional Act creating the government owned Tennessee Valley Authority, May, 1933, designated the government reservation at Wilson Dam as the location for the headquarters of the TVA. In 1980, a court order reassigned the headquarters to Knoxville.

Scottsboro, Alabama, about 63 miles (101 km) from Chattanooga and nicknamed "the Friendly City", is located on Highway 72, 40 miles (64 km) east of Huntsville. It was founded in the mid-1850s and is most famous for the Scottsboro Boys and the Unclaimed Baggage Center, as well as "First Monday," an open-air marketplace held in and around downtown on Mondays following the first weekend of the month.

I-24 connects Paducah, Kentucky, at the mouth of the Tennessee River, with Chattanooga via Clarksville and Nashville. Much of this road's route in Kentucky and Tennessee actually lies outside the Tennessee Valley.